GHTF/SG5/N5:2012
FINAL DOCUMENT
Global Harmonization Task Force
Title: Reportable Events During Pre-Market Clinical Investigations
Authoring Group: Study Group 5 of the Global Harmonization Task Force
Endorsed by: The Global Harmonization Task Force
1h
Date: August 1 0 , 20 12
Dr. Kazunari Asanuma, GHTF Chair
This docwnent was produced by the Global Harmonization Task Force, a voluntary international group of
representatives from medical device regulatory authorities and trade associations from Europe, the United
States of America (USA), Canada, Japan and Australia.
The docwnent is intended to provide non-binding guidance to regulatory authorities for use in the
regulation of medical devices, and has been subject to consultation throughout its development.
There are no restrictions on the reproduction, distribution or use of this document; however, incorporation
of this document, in part or in whole, into any other docmnent, or its translation into languages other than
English, does not convey or represent an endorsement of any kind by the Global Harmonization Task
Force.
Copyright© 2012 by the Global Harmonization Task Force
Reportable Events During Pre-Market Clinical Investigations
Study Group 5 Final Document GHTF/SG5/N5:2012
CONTENTS
1
2
3
4
5
6
7
8
9
Preface................................................................................................................................. 3
Introduction ......................................................................................................................... 4
Scope ................................................................................................................................... 4
References ........................................................................................................................... 5
Definitions........................................................................................................................... 5
Reportable Events ............................................................................................................... 8
To Whom to Report ............................................................................................................ 9
Timing for Reporting .......................................................................................................... 9
Content of Reports ............................................................................................................ 10
Special Conditions ............................................................................................................ 13
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Preface
The document herein was produced by the Global Harmonization Task Force, a voluntary
group of representatives from medical device regulatory agencies and the regulated industry.
The document is intended to provide non-binding guidance for use in the regulation of medical
devices, and has been subject to consultation throughout its development.
There are no restrictions on the reproduction, distribution or use of this document;
however, incorporation of this document, in part or in whole, into any other document, or its
translation into languages other than English, does not convey or represent an endorsement of
any kind by the Global Harmonization Task Force.
August 10th , 2012
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1
Introduction
The objective of adverse event reporting during pre-market clinical investigations is to
improve protection of the health and safety of patients, users and others by identifying safety
issues early in the human use of medical devices so that these can be addressed. These safety
issues can therefore be addressed as soon as possible by modification of the device, revision of
the instructions for use, modification of the clinical investigation plan or withdrawal of the
device from use.
It should be recognized that the requirements for such adverse event reporting should
necessarily be more stringent than post-market vigilance requirements because of the fact that
such medical devices may not have been previously used in humans and are therefore more
likely to be associated with unforeseen physiological or pathological effects.
This document represents a global model, which provides guidance on the types of
adverse events associated with clinical investigations of investigational devices that should be
reported by sponsors to National Competent Authorities (NCAs). It was drafted as a
collaborative effort using the combined expertise of GHTF Study Groups 2 and 5. It incorporates
and supplements existing regulatory requirements existing in the participating member countries
and international standards specifying the planning, conducting and managing of clinical
investigations. However, this guidance may not reflect all current regulatory requirements,
because the present reporting criteria of the participating countries, while similarly intentioned
are not identical. This document therefore provides a model towards which existing systems
should move. The principles laid down in this document should be considered in the
development or amendment of regulatory systems in the participating countries or other
countries.
2
Scope
This guidance aims to set out a uniform system of Adverse Event Reporting globally and
is applicable to pre-market clinical investigations undertaken by, or on behalf of, the
manufacturer to obtain regulatory approval for placing the device on the market and/or premarket investigations that require authorization by the relevant regulatory authority prior to
initiation.
This guidance document concerns only adverse events affecting human research subjects
enrolled in the pre-market phase. When the investigational medical device used in a clinical
study is approved in a particular jurisdiction, the NCA of that country shall apply the post-market
reporting requirements. (GHTF/SG2/N54).
This guidance is supported by the requirements provided in ISO 14155 (Clinical
Investigation of Medical Devices for Human Subjects – Good Clinical Practices) and definitions
have been harmonized to ISO 14155 where possible.
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This document does not deal with reporting by users of investigational devices. Users
should report in accordance with ISO 14155 and any local requirements.
3
References
GHTF final documents
SG1/N29:2005
SG1/N55:2009
SG2/N54:2006
SG5/N2:2007
SG5/N3:2010
Information Document Concerning the Definition of the Term “Medical
Device”
Definition of the Terms Manufacturer, Authorized Representative,
Distributor and Importer
Medical Devices Post Market Surveillance: Global Guidance for Adverse
Event Reporting for Medical Devices
Clinical Evaluation
Clinical Investigations
International standards
ISO 14155:2011
4
Clinical investigation of medical devices for human subjects – Good clinical
practices
Definitions
ADVERSE DEVICE EFFECT: (ISO 14155)
(ADE)
An adverse event related to the use of an investigational medical device.
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate
instructions for use, deployment, implantation, installation, or operation, or any
malfunction of the investigational medical device.
NOTE 2: This definition includes any event resulting from use error or from intentional misuse
of the investigational medical device.
ADVERSE EVENT: (ISO 14155)
(AE)
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs
(including an abnormal laboratory finding) in subjects, users or other persons, whether or not
related to the investigational medical device.
NOTE 1: This definition includes events related to the investigational medical device or the
comparator.
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NOTE 2: This definition includes events related to the procedures involved.
NOTE 3: For users or other persons, this is restricted to events related to investigational medical
devices.
BLINDING/MASKING: (ISO 14155)
Procedure in which one or more parties to the clinical investigation are kept unaware of the
treatment assignment(s).
NOTE:
Single-blinding usually refers to the subject(s) being unaware of the treatment
assignment(s). Double-blinding usually refers to the subject(s), investigator(s),
monitor, and, in some cases, centralized assessors being unaware of the treatment
assignment(s)
CLINICAL INVESTIGATION PLAN (CIP): (ISO 14155)
Document that states the rationale, objective, design and proposed analysis, methodology,
monitoring, conduct and record-keeping of the clinical investigation.
COMPARATOR: (ISO 14155)
Medical device, therapy (e.g. active control), placebo or no treatment, used in the reference
group in a clinical investigation.
DEVICE DEFICIENCY: (ISO 14155)
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety
or performance.
NOTE:
Device deficiencies include malfunctions, misuse or use errors and inadequate labeling
INVESTIGATIONAL MEDICAL DEVICE: (ISO 14155)
Medical device being assessed for safety or performance in a clinical investigation
NOTE 1: This includes medical devices already on the market that are being evaluated for new
intended uses, new populations, new materials or design changes.
NOTE 2: In this standard the terms 'investigational medical device' and 'investigational device'
are used interchangeably.
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INVESTIGATOR: (ISO 14155)
Individual member of the investigation site team designated and supervised by the principal
investigator at an investigation site to perform critical clinical investigation-related procedures or
to make important clinical investigation-related decisions.
NOTE 1: An individual member of the investigation site team can also be called ‘subinvestigator’ or ‘co-investigator’.
PRINCIPAL INVESTIGATOR: (ISO 14155)
Qualified person responsible for the conduct of the clinical investigation at an investigation site
NOTE 1: If a clinical investigation is conducted by a team of individuals at an investigation site,
the principal investigator is the person responsible for leading the team.
NOTE 2: Whether this is the responsibility of an individual or an institution responsibility can
depend on national regulations.
SERIOUS ADVERSE EVENT: (ISO 14155 and GHTF/SG5/N2)
Adverse event that:
a) led to a death;
b) led to a serious deterioration in the health of the subject that either
1) resulted in a life-threatening illness or injury, or
2) resulted in a permanent impairment of a body structure or a body function, or
3) required in-patient hospitalization or prolongation of existing hospitalization, or
4) resulted in medical or surgical intervention to prevent life threatening illness or injury
or permanent impairment to a body structure or a body function;
c) led to foetal distress, foetal death or a congenital abnormality or birth defect.
NOTE:
A planned hospitalization for a pre-existing condition, or a procedure required by the
CIP, without a serious deterioration in health is not considered to be a serious adverse
event.
SERIOUS HEALTH THREAT: (adapted from GHTF/SG2/N54:2006)
Any event type, which results in imminent risk to the study population of death, serious injury,
or serious illness that requires prompt remedial action.
SPONSOR: (ISO 14155)
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Individual or organization taking responsibility and liability for the initiation or implementation
of a clinical investigation.
NOTE:
When an investigator initiates, implements and takes full responsibility for the clinical
investigation, the investigator also assumes the role of the sponsor and is identified as
the sponsor-investigator.
NOTE:
(added for the purpose of this document) The sponsor may be the manufacturer, may
be designated by the manufacturer, or may be designated by the regulatory authority.
SUBJECT: (ISO 14155)
Individual who participates in a clinical investigation
NOTE:
A subject can be either a healthy volunteer or a patient.
UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT: (ISO 14155)
(USADE)
A serious adverse device effect which by its nature, incidence, severity or outcome has not been
identified in the current version of the risk analysis report.
NOTE:
An anticipated serious adverse device effect (ASADE) is an effect which by its nature,
incidence, severity or outcome has been identified in the risk analysis report.
NOTE:
(added for the purpose of this document) This includes unanticipated procedurerelated serious adverse events; that is, serious adverse events occurring during the
study procedure that are unrelated to any malfunction or misuse of the investigational
medical device.
USE ERROR: (ISO 14155)
An act or omission of an act that results in a different medical device response than intended by
the manufacturer or expected by the user.
NOTE 1: Use error includes slips, lapses, and mistakes.
NOTE 2: An unexpected physiological response of the subject does not in itself constitute a use
error.
5
Reportable Events
Events that must be reported by the sponsor are:
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•
•
All serious adverse events affecting the patient, user or a third party, including serious
health threats, regardless of cause or;
Device deficiencies that might have lead to (a) serious adverse event(s) if:
 suitable action had not been taken;
 intervention had not been made; or
 if circumstances had been less fortunate.
In cases where the need to report may be in doubt, the sponsor should make reasonable
efforts to obtain additional information. However as a general principle, there should be a predisposition to report rather than not to report. In the case where opinions on whether an incident
represents a serious adverse event, or the causes of an adverse event, differ between the
Investigator and the Sponsor, both opinions should be reported.
Note: In assessing whether events represent a serious health threat, discussion should be
undertaken with the NCA and consideration should be given to the risk analysis described in the
Clinical Investigation Plan.
6
To Whom to Report
All reportable adverse events, as described in Section 5, must be reported to all the NCAs
responsible for the jurisdictions where the clinical investigation is conducted, according to
applicable requirements in each jurisdiction. NCAs should provide a contact point to sponsors
for reporting.
Note: Reporting to Ethics Committees and all Principal Investigators is also necessary (see ISO
14155 Section 8.2.5).
7
Timing for Reporting
Upon becoming aware of events meeting the reportability criteria defined in section 5,
above, the following guidelines are to be used to establish the timeline under which events of
various levels of severity are to be reported. Note that for the purpose of this document, the date
of awareness refers to the first date on which any employee of the Sponsor, authorized
representative or Contract Research Organisation for the investigation, becomes aware of a
serious adverse event.
7.1
Such serious adverse events which have been determined to represent a serious health
threat to the study population must be reported by the sponsor to the NCAs of all
jurisdictions in which centres participating in the investigation are located within 48
hours following the determination that the serious health threat exists.
7.2
To be reported as soon as possible, but not later than 10 elapsed calendar days
following the date of awareness of the event:
.
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• Unanticipated Serious Adverse Device Effects
• Serious adverse events, other than unanticipated serious adverse device effects,
resulting in death, or resulting in a serious deterioration in the health of the subject
that either:


resulted in a life-threatening illness or injury
resulted in a permanent impairment of a body structure or a body function
• Serious adverse events, other than unanticipated serious adverse device effects, that
have led to fetal distress, fetal death or a congenital abnormality or birth defect
7.3
To be reported as soon as possible, but not later than 30 elapsed calendar days
following the date of awareness of the event:
• Serious adverse events, other than unanticipated serious adverse device effects,
resulting in a serious deterioration in the health of the subject that either:


required in-patient hospitalization or prolongation of existing hospitalization
resulted in medical or surgical intervention to prevent life threatening illness
or injury or permanent impairment to a body structure or a body function
• Any device deficiency that might have led to a serious adverse event if either:
 suitable action had not been taken;
 intervention had not been made; or
 circumstances had been less fortunate.
If, after becoming aware of a potentially reportable adverse event, there is uncertainty
about whether the event is reportable, the sponsor must submit a report within the timeframe
required for that type of event.
8
Content of Reports
Notification of reportable events should include the following information:
(Mandatory information highlighted in yellow, “yes/no” indicates whether that information is
mandatory for that type of report, blanks indicate information that should be provided if
available but may not be mandatory)
Section
Type of Information
Initial
Rep.
Final
Rep
Comments / Field
content
Administrative
Information
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Section
Type of Information
Report type
Title of the clinical investigation
Sponsor’s clinical investigation plan
identifier
All NCAs’ clinical investigation
identifiers
Report reference number
List of NCAs this report is being
sent to
NCA event reference number ( if
applicable)
Contact details of sponsor
Date of report
Manufacturer Information
Expected date of next report if this
is not a final report
Initial
Rep.
Final
Rep
Comments / Field
content
Yes
Yes
(Initial, Follow-Up,
Final, or combined
Initial/Final)
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Complete address
incl. contact point
Device
Information
Name of the device/ model number
Serial number/lot number (if
applicable)
Accessories ( if applicable )
Number of devices used by the
investigator
Number of patients enrolled in the
site
Number of patients involved in this
incident – if applicableNumber of patients exposed to this
device – if reusable deviceNumber of patients treated in the
study
Event
information /
serious health
threat
information
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Section
Type of Information
Initial
Rep.
Final
Rep
Center/institution/investigator
Date the adverse
event/events/device deficiency
occurred
Date of awareness by investigator
Date of awareness by sponsor/Date
of determination of existence of
serious health threat by sponsor
Yes
Yes
Yes
Yes
Yes
Yes
Information on the person affected
Investigation arm for comparative
investigations (if known)
Description of the event/device
deficiency
*
Patient, user, other
person
Yes
Yes
Yes
Yes
Outcome of event
Yes
Yes
Anticipated/Unanticipated
Yes
Yes
Relatedness of Event according to
sponsor
Yes
Yes
Relatedness of Event according to
Investigator
Patient ID code (if applicable)
Yes
Yes
Yes
Yes
Year of birth (if known)
Gender (if known)
Weight (if known)
Comments / Field
content
Yes
No
Select from picklist
according to ISO
14155 SAE
definition (e.g.
“serious
deterioration – perm.
impairment”
Select from picklist
of 2
Select from picklist
of 3 (device related,
procedure related,
other; each scaled 14 based on relative
certainty) *
Select from picklist
of 3 (device related,
procedure related,
other; each scaled 14 based on relative
certainty) *
Only if affected
person is the patient
Relatedness: 1 = unrelated, 2 = possibly related, 3 = probably related, 4 = definitely related
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Section
Type of Information
Initial
Rep.
Final
Rep
Comments / Field
content
Yes
Includes all
investigations done
and their results –
must include both
opinions of sponsor
and investigator if
these remain
different
Action taken by investigator (if
applicable)
Initial action by sponsor (if
applicable)
For final report
Final assessment including
relatedness and rationale
No
Corrective action taken (or
planned?) Including timeline
Frequency of similar events
observed to date in the treatment
group.
Yes
Frequency of similar events in
comparator groups (in the control
arm if applicable, in the historic
control as mentioned in the protocol,
from other sources used in the risk
analysis).
Yes
Opinion of the Sponsor on the
acceptability of the SAE and of its
current frequency in this clinical
trial with rationale.
Patient/Subject Outcome
Actions to be taken to the clinical
investigation
9
i.
Yes
Yes
Yes
Yes
Yes
e.g. suspension,
early termination,
other, none
Special Conditions
Medicinal product/device, biologic product/device combinations: adverse
events/device deficiencies for combination products that involve drugs or biologics acting
ancillary to an investigational medical device should be reported in line with the
principles set out in this document
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ii.
Controlled clinical investigations: where an unblinded controlled clinical investigation
is being carried out using a marketed medical device as the control, adverse events/device
deficiencies of the unmarketed device should be carried out in line with the principles set
out in this document. The adverse events involving the marketed device should be
reported to the NCA in line with GHTF/SG2/N54 “Global Guidance for Adverse Event
Reporting for Medical Devices”.
iii.
Double blinded controlled clinical investigations: where a double blinded controlled
clinical investigation is being carried out using a marketed medical device as the control,
all adverse events/device deficiencies should be reported to the NCA in line with the
principles set out in this document. The data should normally not be unblinded, unless
requested by the NCA.
iv.
Implantable medical devices: Only SAEs that are device deficiencies occurring with
devices implanted in a patient in a clinical investigation setting, where the investigation
has since closed, should be reported according to the principles outlined above.
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FIGURE I
Start
YES
Is there a serious
health threat?
Report as soon as possible, but not later
than 48 hrs after the sponsor
determines that this is a serious
health threat
NO
NO
Is there an adverse
event?
YES
Was there a device
deficiency that might
have led to an SAE if
suitable action had not
been taken, intervention
not been made, or
circumstances had been
less fortunate?
NO
Not reportable
YES
Report as soon as possible, but not later
than 30 elapsed calendar days
following the date of awareness of the
event
YES
Is there a serious
adverse event?
Was it related to the use
of the investigational
device?
NO
NO
YES
Not reportable
NO
Was it anticipated
reported as soon as possible , but not
later than 10 elapsed calendar days
following the date of awareness of the
event
YES
Did it result in:
- death
- fetal distress, fetal death, or a congenital
abnormality or birth defect
- serious deterioration in the health of the subject
that either:
- resulted in life-threatening illness of injury, or
- resulted in permanent impairment of a body
structure or body function?
NO
reported as soon as possible , but not
later than 30 elapsed calendar days
following the date of awareness of the
event
YES
SAE: Serious Adverse Event
August 10th , 2012
reported as soon as possible , but not
later than 10 elapsed calendar days
following the date of awareness of the
event
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